Prostaglandin E2 Signaling: Alternative Target for Glioblastoma?

Abstract

Elevated cyclooxygenase-2 (COX-2) and the associated inflammation within the brain contribute to glioblastoma development. However, medical use of COX inhibitors in glioblastoma treatment has been limited due to their well-documented vascular toxicity and inconsistent outcomes from recent human studies. Prostaglandin E2 (PGE₂) has emerged as a principal mediator for COX-2 cascade-driven gliomagenesis. Are PGE₂ terminal synthases and receptors feasible therapeutic targets for glioblastoma?

Keywords: EP receptors; PGE(2); glioblastoma; gliomagenesis; mPGES-1; neuroinflammation.

Figure 1. PGE₂ Signaling through EP Receptors Promotes Gliomagenesis

(A) Biosynthesis of prostaglandin E2 (PGE₂). With various stimuli, arachidonic acid is liberated from membrane phospholipids by phospholipase A2 (PLA2), then converted into prostaglandin H2 (PGH₂) – an intermediate molecule – by cyclooxygenase (COX). Unsteady PGH₂ is further catalyzed by tissue-specific prostanoid synthases to five prostanoid products comprised of prostaglandins PGE₂, PGD₂ and PGF_2α, thromboxane A2 (TXA₂), and prostacyclin PGI₂. The COX is the checkpoint enzyme in the synthesis of prostanoids and in mammals has two isoforms – COX-1 and COX-2. The COX-1 is constitutively expressed in most normal tissues to synthesize homeostatic prostanoids that are essential for maintaining many physiological functions; whereas the COX-2 is present at low levels under normal conditions but is rapidly and robustly induced to mediate various pathological processes that are usually associated with severe inflammatory reactions in response to tissue injuries and other detrimental stimuli [7]. (B) Prostanoids through a suite of G protein-coupled receptors (GPCRs) regulate a diversity of physiological and pathological events, e.g., inflammatory responses by prostaglandins, particularly PGE₂; vasodilation by PGI₂; vasoconstriction by TXA₂. Two receptors (DP1 and DP2) for PGD₂ have been identified up to date and four for PGE₂ (EP1, EP2, EP3 and EP4), and each of the other three prostanoids acts on a single receptor – FP for PGF_2α, IP for PGI₂, and TP for TXA₂. Multiple molecular signaling pathways have been proposed to mediate the effects of PGE₂ on the regulation of glioblastoma cell survival, proliferation, migration, invasion, angiogenesis, immunosuppression, etc. Only the major pathways are indicated here by different colors. Abbreviations: AC, adenylyl cyclase; ATP, adenosine triphosphate; β-cat, β-catenin; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase; cPGES, cytosolic prostaglandin E synthase; DAG, diacylglycerol; EGFR, epidermal growth factor receptor; EPAC, exchange protein directly activated by cAMP; EPs, prostaglandin E2 receptors; ERK, extracellular signal-regulated kinase; F-actin, filamentous actin; GSK3β, glycogen synthase kinase 3β; IP3, inositol 1,4,5-trisphosphate; JNK, c-Jun N-terminal kinase; MEK, mitogen-activated protein kinase kinase; mPGES, membrane-associated PGES; Pfn-1, profilin-1; PGE₂, prostaglandin E2; PGH₂, prostaglandin H2; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; RAF, rapidly accelerated fibrosarcoma kinase.